The Receptor for Advanced Glycation Endproducts (“RAGE”), a multi-ligand member of the immunoglobulin superfamily of cell surface molecules, has been implicated in amplification of proinflammatory responses (1). S100/calgranulins, proinflammatory signal transduction ligands of the receptor, are enriched in joints of subjects with rheumatoid arthritis (“RA”) (2-4). Members of this family of molecules, long-associated with classic immune/inflammatory disorders (5-6), may be released by activated inflammatory effector cells such as monocytes (7), thereby freeing them to engage cell surface RAGE and amplify host inflammatory responses. Indeed, accumulation of S100/calgranulins in synovial fluid and plasma of subjects with RA has been correlated with indices of disease severity, such as bony erosions (4).
Recent studies have highlighted the possibility that polymorphisms within key domains of RAGE may influence its function, so that under conditions of increased ligand accumulation, individuals may be predisposed to heightened inflammatory responses (8-9). Importantly, a polymorphism of the RAGE gene has been identified within the V-type immunoglobulin domain in the extracellular region of the receptor, consisting of a glycine to serine change at position 82 (8). In previous studies, it was found that the ligands of RAGE, including S100/calgranulins, engage the V-domain of the receptor and activate signal transduction pathways, thereby modulating gene expression (1,10-14).